Background:
The microtubule is composed of αβ-tubulin heterodimers and is an attractive target for the design
of anticancer drugs. Over the years, various compounds have been developed and their effect on tubulin polymerization has
been studied. Despite a great efforts to make an effective drug, no drug has been introduced which inhibit colchicine binding
site.
Objective:
In the current work a series of pyrimidine derivatives were designed and synthesized. Furthermore their cytotoxic
activities were evaluated and molecular docking studies were performed.
Methods:
Twenty compounds of pyrimidine were synthesized in 2 different groups. In the first group, 4,6-diaryl pyrimidine
was connected to the third aryl group via thio-methylene spacer. In the second group, this linker was substituted by S-CH2-
triazole moiety. The cytotoxic activity of these compounds was evaluated against 4 different cell lines (HT-29, MCF-7,
T47D, NIH3T3).
Results:
Compounds 6d, 6m, 6p showed potent cytotoxic activity against MCF7 cancerous cell lines. Between these compounds, compound 6p did not show cytotoxic activity against NIH- 3T3 (normal cell) cell line. Docking studies show that
these compounds occupy colchicine binding site in tubulin protein and probably their anticancer mechanism is inhibition of
tubulin polymerization.
Conclusion :
Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on pyrimidine
scaffold as antimitotic agents. Attention to the selectivity index of 6p on MCF7 cell line could be valuable in design new
chemical agents for treatment of breast cancer.
Design, eco-friendly synthesis, molecular modeling and anticancer evaluation of thiazol-5(4H)-ones as potential tubulin polymerization inhibitors targeting the colchicine binding site